3/29/2012. Thyroid cancer- what s new. Thyroid Cancer. Thyroid cancer is now the most rapidly increasing cancer in women

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1 Thyroid cancer- what s new Thyroid Cancer Changing epidemiology Molecular markers Lymph node dissection Technical advances rhtsh Genetic testing and prophylactic surgery Vandetanib What s new? Jessica E. Gosnell MD Postgraduate course March Most thyroid nodules are benign thyroid nodules occur in 77% of the world s population palpable thyroid nodules occur in about 5% of women and 1% of men in the US more common in women, advancing age, iodine deficiency, family history and radiation exposure high resolution ultrasound can detect nodules in 19-67%, with increasing rates in women and the elderly (Tuttle and Lehoeuf, Endo Metab N Am) (ATA revised guidelines for Thyroid Nodules, Thyroid 2009) 32 2 Thyroid cancer is now the most rapidly increasing cancer in women Approximately 37,200 new cases of thyroid cancer were diagnosed in 2009 Yearly incidence 3.6 per 100,000 in > 8.7 per 100,000 in 2002 Most of the change is attributed to increases in papillary thyroid cancer, which comprises 90% of all thyroid cancers Almost half of the rising incidence consisted of tumors <1cm

2 Thyroid nodules: differential diagnosis Thyroid cancer: History Symptoms of hypo, hyperthryoidism Local symptoms in the neck dysphagia, dyspnea, dysphonia neck pain family history of thyroid or other cancers exposure to ionizing radiation to the head and neck (Gosnell and Clark, Management of thyroid nodules, in Cameron s Current Surgical Therapy, 10th ed, 2010) Primary thyroid cancer Papillary 80% Follicular 13% Medullary 4% Hurthle 3% Anaplastic <1% Most thyroid cancers are biochemically silent TSH is the signal best test to assess for thyroid dysfunction T3, T4 as indicated thyroglobulin Suh et al., Serum thyroglobulin is a poor diagnostic biomarker of malignancy in follicular and Hurthle-cell neoplasms of the thyroid. 366 pts with follicular/hurthle cell lesions Tg levels>500mug/l had positive predictive value of 0.75 (Hundahl, Cancer 1998) (Suh et al., Am J Surg 2010Jul;200:41)

3 FNA biopsy for thyroid nodule FNA: typical papillary thyroid cancer FNA biopsy Benign (70%) > 90% accurate Malignant (<10%) Indeterminate/suspicious (5-10%) Nondiagnostic (<10%) 10 50% risk of cancer10 50% risk of cancer Total thyroidectomy (lobectomy) "Diagnostic" thyroidectomy Orphan Annie eyes Need for more accurate diagnostic tests than FNA cytology! Indeterminate FNA cytology Multi-step tumorigenesis of thyroid cancer follicular cell lesion Hurthle cell lesion (Learoyd, WJ Surg 2000) 12 3

4 Molecular marker testing should be considered for patients with indeterminate FNAs American Thyroid Association guidelines: 2006: Many molecular markers have been evaluated to improve diagnostic accuracy for indeterminate nodules, but none can be recommended because of insufficient data 2009: Recent large prospective studies have confirmed the ability of genetic markers (BRAF, Ras, RET/PTC) and protein markers (galectin-3) to improve preoperative diagnostic accuracy for pts with indeterminate FNAs not yet widely applied in clinical practice The role of diagnostic surgery Indicated for follicular or Hurthle cell neoplasms Indicated for patients with worrisome clinical findings growing nodules, risk factors for thyroid cancer Should be considered for nodules > 4cm The role of intraoperative frozen section useful for nodules suspicious for papillary thyroid cancer but not follicular or Hurthle cell nodules useful for cervical lymph nodes, parathyroid glands (Livolsi, Surgical Pathology of the Thyroid, 2nd ed, 2007) Treatment of thyroid cancer- DTC (differentiated, non-medullary) Treatment of differentiated thyroid cancer Surgery Most patients can be cured with initial multi-modal therapy Radioiodine ablation 20-30% pts recurrent/metastatic disease TSH-suppression tx

5 Response to radioiodine for distant metastases Advances in radioiodine ablation In euthyroid patients treated with rhtsh, mean 131I effective half-life is shorter by 31% than in hypothyroid patients who undergo withdrawal This treatment decreases the radiation doses delivered to extrathyroidal tissues and permits a shorter and more predictable length of hospitalization. rhtsh stimulated treatment -Lower radiation retention/toxicity Remy et al, J Nuclear Med year survival: 76 vs 25% (Ronga, 2004) Prophylactic vs. therapeutic central lymph node dissection Controversial!! Medullary thyroid cancer Early diagnosis/treatment Calcitonin screening Genetic testing Prophylactic surgery High incidence of nodal metastases Many do not grow or spread Newer data suggests increased thyroglobulin and recurrence CLND increases risk to parathyroids and RLN Several prospective randomized studies

6 Medullary thyroid cancer (ATA guidelines MTC 2009, Kloos et al. Thyroid ;19 (6):565) Anaplastic thyroid cancer Early diagnosis Multimodal therapy! Swedish study of 33 patients treated with adriamycin for 4 wks, then underwent surgical resection followed by 2 weeks of radiation and chemotherapy (Tennvall et al, Cancer 1994) Definitive resection in 70% Local control in 48% 4 patients had disease at 2yr Only 24% died of local failure Mayo study of 10 patients with locally confined ATC with resection, then chemotherapy (doxorubicin with docetaxal) and IMRT (Foote et al, Thyroid 2011) Overall survival at 1 and 2 yrs was 70% and 60% Treatment for recurrent thyroid cancer Operative resection Radioiodine ablation External beam radiation Adjunctive approaches Chemotherapy Novel agents Operative treatment advances for recurrent DTC Nerve monitoring Improved localization Decreased complications Retrospective 295 pts CLND, decreased rate of transient hypocalcemia, same rate of other complications (Shen et al, Arch Surg 2010)

7 Reoperative neck surgery: bluedye localization Advances in radiation treatment Dose planning simulations intensity modulated radiation therapy (IMRT) Gamma knife Sippel et al, World J Surg 2009 First 10 patients, all successful, no complications Adjunctive approaches to recurrent/metastatic disease Ethanol injection Radiofrequency ablation (RFA) Vertebroplasty and kyphoplasty Failure of traditional systemic chemotherapy Doxorubicin 17% vs 26% (12% complete response) Bleomycin, Doxorubicin & Cisplatin 42% response, median survival 11 months Etopside 0% response (failure to recruit) clinical trials initiated 5 had results published 0 reached full enrollment (Sherman et al, 2005)

8 Advances in the treatment of metastatic thyroid cancer Oncogenes in human thyroid cancer Re-differentiation therapy Therapy targeting cancer-related genes or their products 29 (Clark, Duh and Kebebew, 2005) 30 Receptor blockers: rationale VEGF one of the key tyrosine kinases in endothelial cell proliferation and survival c-kit and PDGF mutated in rare cancers (GIST, CMML) or overexpressed in others (lung, breast, melanoma,etc) RET mutated or activated by rearrangement in subsets of thyroid cancer, some MTC and PTC Clinical trials for thyroid cancer Valproic acid histone deaceylase inhibitor (HDAC) Decitabine DNA methylase inhibitor Everolima mtor inhibitor LBH589 HDAC inhibitor Sorafenib receptor tyrosine kinase inhibitor (TKI) Sunitinib TKI Pazopanib TKI Fostamatinib TKI Bortezomib proteasome inhibitor Vemurafenib BRAF inhibitor RAD001 mtor inhibitor Lithium glycogen synthase kinase inhibitor rad-p53 gene therapy E7080 multi-kinase receptor inhibitor Vandetanib TKI VB-111 anti- angiogenic agent Alpha lipoic acid antioxidant XL 147 P13K inhibitor

9 Drugs approved for Thyroid Cancer Adriamycin PFS Vandetanib- April 2011 Suggested reading Tuttle et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid volume 19 Issue 11, Nov 4, Gosnell and Clark. Management of Thyroid Nodules. In Cameron s Current Surgical Therapy, 10th ed Questions? 35 9

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